Chiral Supramolecular Polymer Formed via Host-Guest Complexation of an Octaphosphonate Biscavitand and a Chiral Diammonium Guest

Abstract

Chiral supramolecular polymers were constructed through the host-guest complexation of an octaphosphonate biscavitand and a chiral diammonium guest. Isothermal titration calorimetry determined that host-guest complexation was enthalpy- and entropy-favored with high binding constants. Diffusion-ordered NMR spectroscopy and viscometry of the host-guest solution revealed that supramolecular polymerization occurred, which most likely followed a ring-chain mechanism. The cyclic oligomers and the supramolecular polymer chains were visualized by atomic force microscopy. Circular dichroism was observed when the octaphosphonate biscavitand and the chiral diammonium guest were mixed, which suggested that chirally twisted supramolecular polymers were formed.

Cavitand, Supramolecular polymer, Chiral polymer

1. Introduction

Chirality introduces an advanced playground in the field of synthetic polymer chemistry.^1–3 Stereogenic centers, axes and planes can be installed on polymer backbones, offering chiral polymers with novel functions such as chiral separation,^4–7 catalysis,^8–11 sensing,¹² etc., which are associated with their chirality.^13–16 The control of chirality in polymer structures has become a key subject in polymer chemistry. Many efforts have been devoted to the synthesis of chiral polymers. In contrast to chiral conventional polymers, the noncovalent synthesis of chiral supramolecular polymers expands synthetic flexibility. Therefore, chiral supramolecular polymers have become potential alternatives to chiral conventional polymers for the development of unique chiroptical behaviors encompassing chiral amplification,^17–24 chiral sorting,^25–30 etc.^31–34 Chiral supramolecular polymers are formed through the self-assembly of chiral monomer units on which various stereogenic centers, axes and planes can be installed, which are thus highly designable and synthetically accessible.^35–40 Various host-guest interactions are employed for the self-assembly of chiral monomer units. Cyclodextrins,^41–43 pillararenes,^44–46 etc. have been demonstrated to form chiral supramolecular polymers.⁴⁷

Resorcinarene-based cavitands are known to be synthetic receptors with enforced cavities where various guest molecules are encapsulated.^48–51 Various interannular bridging groups connect the phenolic hydroxyl groups of a resorcinarene platform, in which the size, shape, and dimension of the cavities varies. Therefore, the choice of bridging groups determines the molecular recognition abilities of cavitands. Phosphonate cavitands possess four phosphonate interannular bridges, where four hydrogen bond accepting P=O groups point inward at the upper rim of the cavity.^52–55 Therefore, phosphonate cavitands provide convincing hydrogen bonding environments where hydrogen-bonding guests such as ammonium ions and alcohols are encapsulated with very high binding constants.^56–61 These high binding constants have particular potential for supramolecular polymerization. Although linear, branched, and grafted supramolecular polymers have been reported by Dalcanale thus far,^62–64 cavitand-based chiral supramolecular polymers remain limited.

During a course of studies in supramolecular chemistry,^65–77 we have shown that feet-to-feet-connected octaphosophonate biscavitand 1 is particularly appealing for allosteric guest binding (Figure 1a).^77–79 The biscavitand possesses a helically twisted conformation where the (P)- and (M)-forms are dynamically interchanged at room temperature (Figure 1b).^80,81 We envisioned that the iterative host-guest complexation of a chiral ditopic guest molecule G1 to ditopic biscavitand 1 can drive helically twisted chiral supramolecular polymer chains. Herein, we report more of our efforts toward the synthesis of the chiral supramolecular polymer poly-1•G1. The supramolecular polymerization of 1 and G1 most likely followed a ring-chain mechanism. Atomic force microscopy (AFM) was used to visualize the polymeric and cyclic forms. The helicity of the supramolecular polymer chain poly-1•G1 was cooperatively directed by the stereogenic center of G1, which formed chiral supramolecular chains.

Figure 1.

(a) Structures of octaphosphonate biscavitand 1 and chiral diammonium guest (R,R or S,S)-G1. (b) Schematic illustration of the P/M interconversion of 1 and supramolecular polymerization via iterative host–guest complexation between 1 and G1.

2. Results and Discussion

The synthesis of bisammonium guest molecules (R,R)- and (S,S)-G1 is shown in Scheme 1. Ester formation of (R)- and (S)-2⁸² and 1,4-diboromomethylbenzene gave rise to chiral diesters (R,R)- and (S,S)-3 in moderate yields. Deprotection of (R,R)- and (S,S)-3 was carried out by treatment with hydrochloric acid in dioxane. Ammonium salts (R,R)- and (S,S)-4 were treated with silver hexafluorophosphate to afford (R,R)- or (S,S)-G1. A monotopic guest (S)-G2 was prepared in the same manner. Benzyl ester formation of (S)-2 by the treatment of benzyl bromide gave rise to (S)-5, followed by deprotection, and the subsequent counteranion exchange reaction produced (S)-G2.

Scheme 1.

Synthesis of ditopic guest molecules (R,R)- and (S,S)-G1, and a monotopic guest molecule (S)-G2.

The molecular association between 1 and (S,S)-G1 was studied by ¹H NMR spectroscopy (Figures 2, S19, and S20). The N-CH₃ and CH-CH₃ protons appeared at 2.8 and 1.5 ppm, respectively. Upon the addition of 1 into a solution of (S,S)-G1, the protons shifted to −0.14 and 1.36 ppm at −50 °C, respectively. The remarkable upfield shifts of −2.66 and −0.14 ppm are characteristic of the formation of host-guest complexation between the ammonium group and the phosphonate cavitand unit, where the ammonium group is located deep inside the aromatic cavity, experiencing a strong shielding effect.⁷⁸ The methyl groups adjacent to the stereogenic centers also experienced the shielding effect of the phenyl rings at the phosphonate groups. The methyl groups most likely generate steric interactions with the cavitand units in a chiral fashion. Concordant results were observed in ¹H NMR studies of a mixture of 1 and (R,R)-G1 (Figures S21–S23) and 1 and (S)-G2 (Figures S24–S26), leading to a conclusion that 1 and (R,R)-G1 and 1 and (S)-G2 formed a supramolecular complex in solution.

Figure 2.

Expanded view of ¹H NMR spectra highlighting the appearance of new resonance peaks when (S,S)-G1 (1.0 × 10⁻³ mol L⁻¹) was exposed to 1 at −50 °C in CD₃OD/CDCl₃ (5/5, v/v). (a) (S,S)-G1, (b) (S,S)-G1 with 0.5 equiv. of 1, (c) (S,S)-G1 with 1.0 equiv. of 1, and (d) 1 (1.0 × 10⁻³ mol L⁻¹).

Job plots were generated using fluorescence titration, which gave rise to a peak at a host-guest ratio of 1:1, which drove the formation of the supramolecular polymer poly-1•G1 (Figure 3). Note that reasonably high apparent binding constants (K_a) of 1 with (S,S)-G1 and (R,R)-G1 were determined to be 110,000 ± 4,000 M⁻¹ and 134,000 ± 6,000 M⁻¹ in methanol by applying a simple 1:1 association model using isothermal titration calorimetry (Figures S27 and S28). The thermodynamic parameter of the intermolecular association between 1 and G1 resulted in enthalpic and entropic contributions: ΔH = −2.66 ± 0.02 kcal mol⁻¹ and ΔS = 14 ± 1 cal mol K⁻¹ for (S,S)-G1; ΔH = −3.01 ± 0.03 kcal mol⁻¹ and ΔS = 13 ± 1 cal mol K⁻¹ for (R,R)-G1. Supramolecular polymerization through host-guest complexation is an enthalpy- and entropy-driven process, where the desolvation of the solvated cavity presumably resulted in the positive entropic contributions. ITC titration experiments of 1 and (S)-G2 gave detailed insight into the binding event between the biscavitand and the ammonium guest (Figures S29 and S30). Negative cooperativity was observed in the 1:2 binding of 1 and (S)-G2, which is consistent with the binding behavior of our previously reported biscavitand molecules.⁷⁷

Figure 3.

Job plots for (a) 1 and (S,S)-G1 and (b) 1 and (R,R)-G1 in methanol. The total concentrations of 1 and G1 were consistently maintained at 5.00 × 10⁻⁵ mol L⁻¹ at 25 °C in methanol. ΔI′ indicates |I − I₀[G1]/([1] + [G1])|.

The polymer growth process was corroborated by the diffusion ordered NMR (DOSY) technique and solution viscometry. Figures 4a and S31 and Table S1 shows that the diffusion coefficients of 1 with (S,S)-G1 and 1 with (R,R)-G1 depended on the concentration although constant D value was observed in the solution of a mixture of 1 and (S)-G2. Upon concentrating the solution of 1 and G1 in methanol-d₄ with 50% chloroform-d₁, the diffusion coefficients (Ds) gradually decreased, reaching a value of 1.75(1) × 10⁻¹⁰ m² s⁻¹ ((S,S)-G1) and 1.77(2) × 10⁻¹⁰ m² s⁻¹ ((R,R)-G1) at a concentration of 10.0 mmol L⁻¹ (Table S1). Based on a diffusion coefficient of 2.89(2) × 10⁻¹⁰ m² s⁻¹ for 1, the average degree of polymerization can be estimated by the comparison of the diffusion coefficients of 1 and poly-1•G1 using the following equation: DP = (D_monomer/D_polymer).³ Assuming the polymer was hydrospherical, the DP was roughly estimated to be 5-mer at a concentration of 10.0 mmol L⁻¹. This low DP value suggests that the host-guest complexation between 1 and G1 might form cyclic species as intermediates in a millimolar concentration range.

Figure 4.

(a) Diffusion coefficients of 1 (open circle) and poly-1•(S,S)-G1 (filled circle) in chloroform-d₁-methanol-d₄ (50:50 v/v). (b) Solution viscosities of 1 (open circle), (S,S)-G1 (open triangle) and poly-1•(S,S)-G1 (filled circle) at 25 °C in chloroform-methanol (50:50 v/v). (c) Log-log plot of (b).

To gain further insights into the supramolecular polymerization, the solution viscosities of 1, G1, and 1•G1 were measured (Figure 4b). The solution viscosities of 1 and G1 increased linearly without a critical polymerization concentration (CPC) upon concentrating their solutions. In contrast, the solution viscosity of poly-1•G1 increased more evenly at low concentrations. The log-log plot of the specific viscosities and the solution concentrations resulted in a CPC of 19 mmol L⁻¹ (Figure 4c). Below the CPC, a slope value of 0.94 suggests that the supramolecular polymer chains of poly-1•G1 were too short to be entangled in the dilute solution regime. Above the CPC, long supramolecular polymer chains come in contact to create viscous drag. However, a slope value of 2.02 is obviously lower than the scale exponent given by Cates,⁸³ implying that the polymer chains are too short to be entangled.

We have recently reported that supramolecular polymerization favors a flexible monomer over a rigid monomer in a ring-chain competition mechanism, where a rigid monomer prefers to form cyclic oligomers, whereas a flexible monomer favors polymerization.⁶⁹ In this aspect, a lack of conformational flexibility in 1 and G1 can stabilize cyclic forms of poly-1•G1. Therefore, above the CPC, the cyclic forms of poly-1•G1 most likely exist, which compete with the linear supramolecular polymer chains in solution. Thus, the ring-chain competition of poly-1•G1 results in a slope value of less than Cates’s prediction.

A methanol solution of poly-1•G1 was spin-coated on a highly oriented pyrolytic graphite (HOPG) surface. Fine morphologies of the supramolecular polymer poly-1•G1 were found on the surface by atomic force microscopy (AFM) (Figure 5a). The supramolecular polymer poly-1•G1 formed well-developed worm-like fibers with many bundles and branches. The profile of the fibers gave rise to a uniform average height of 1.8 ± 0.2 nm with a broad width of 31 ± 7 nm. The supramolecular polymer chains of poly-1•G1 were well grown with lengths ranging from 22 nm to more than 200 nm. No polymeric fibers were visualized in the AFM images of (S,S)-G1 and 1 (Figure S32), indicating a combination of the ditopic host and the ditopic guest played a key role for the formation of the supramolecular polymers.

Figure 5.

AFM images (a, b) of poly-1•(S,S)-G1 prepared on highly oriented pyrolytic graphite. c) Height profile of the supramolecular polymer poly-1•(S,S)-G1. d) Calculated structure of (S)-G2₂•1₂•(S,S)-G1. The blue circles highlight the cyclic morphologies.

To estimate the size and dimension of poly-1•G1, the repeating unit was modeled with (S)-G2₂•1₂•(S,S)-G1 by PM6 semiempirical molecular orbital calculations. The optimized structure in Figure 5d illustrates that the supramolecular polymer chain possesses a repeating length of 2.9 nm and a chain width of 1.7 nm. The height value is consistent with the molecular width of (S)-G2₂•1₂•(S,S)-G1, whereas the broad width is obviously larger than the molecular width. Thus, the supramolecular chains most likely spread well, which produced bundles consisting of approximately eighteen polymer chains. The DP of the supramolecular polymers is calculated by the length of the repeating unit, ranging from 8 to more than 71. Accordingly, long fibers are developed in the solid state due to strong host-guest interactions.

Biscavitand 1 is known to adopt (P)- and (M)-helical conformations, which rapidly interchange between each other.⁸⁰ The stereogenic centers of G1 can direct the helicity of 1 through host-guest complexation. 1 possesses an absorption band at 273 nm (Figure 6a). The addition of (S,S)-G1 induced weak minus-to-plus bisignate-induced circular dichroism (ICD), suggesting that the (P)- and (M)-helical conformations of 1 were slightly biased. The supramolecular polymerization of 1 with (R,R)- and (S,S)-G1 resulted in an excellent mirror image relationship. The ICD was associated with the stoichiometries of (S,S)-G1 to 1 (Figure 6b). As the guest stoichiometry increased, the ICD at 270 nm gradually intensified and peaked at a host-guest ratio of 1:1. An excess amount of (S,S)-G1 reduced the ICD intensity. In addition, the addition of monotopic (S)-G2 resulted in the 1:2 host-guest complex 1•(S,S)-G2₂ (Figure S29), resulting in very weak ICD, which indicates that the chiral guest complexation did not drive the one-handed helical conformation of 1. These findings suggest that the supramolecular polymer chain has a cooperative impact on directing the helicity of the repeating unit 1 in the supramolecular polymer chain. Given that the helicity excess was most likely low due to the weak ICD, supramolecular polymerization induces the helically twisted supramolecular polymer chain with many defect points at which the (P)- and (M)-conformations are twisted with each other.

Figure 6.

(a) CD spectra of 1 (2.0 × 10⁻⁴ mol L⁻¹) with one equivalent of (R,R)-G1 (blue solid line), with (S,S)-G1 (red solid line, a–e: 0.33, 0.66, 1.00, 1.33, and 1.66 equiv), and with two equivalents of (S)-G2 (broken line) at 25 °C in methanol. UV spectrum of 1 (4.4 × 10⁻⁵ mol L⁻¹) (black solid line) at 25 °C in methanol. (b) CD intensities at 270 nm. A quartz cuvette with an optical path length of 1 mm was used.

3. Conclusion

In conclusion, we demonstrated that the interactive host-guest complexation between octaphosphonate biscavitand 1 and chiral bisammonium guest G1 resulted in the supramolecular polymer poly-1•G1. In solution, the ring-chain competition mechanism most likely participates in the growth of the supramolecular polymer chain; however, the long and uniform supramolecular fibers were grown in the solid state. The helicity of the supramolecular chain is directed by the stereogenic center of G1 in a cooperative manner. Therefore, the cooperativity in the guest complexation of octaphosphonate biscavitand 1 primarily has the potential to control higher-order chiral supramolecular architectures.

4. Experimental

General

All chemicals and solvents were purchased from Nacalai Tesque Inc., Kanto Chemical Co., Ltd., Wako Pure Chemical Co., Ltd., Tokyo Kasei Kogyo Co., Ltd., and Sigma–Aldrich Co., Ltd. and were used as received without further purification. ¹H and ¹³C spectra were recorded on a VARIAN Mercury 300 spectrometer or a JEOL ECA500 spectrometer. Chemical shifts are quoted as parts per million (ppm) relative to chloroform (chloroform-d₁, δ = 7.26 ppm for ¹H and 77.2 ppm for ¹³C) and methanol (methanol-d₄, δ = 3.31 ppm for ¹H and 49.0 ppm for ¹³C). Infrared (IR) spectra were recorded on a JASCO FT/IR-4600 spectrometer with a ZeSe ATR accessory. Solution viscosity was recorded on an Anton Paar Microviscometer Lovis 2000ME. High-resolution mass spectra (HRMS) were recorded on a Thermo Fisher Scientific LTQ Orbitrap XL using electron spray ionization (ESI). Melting points were measured with a Yanagimoto micro melting point apparatus and are uncorrected. UV/vis absorption spectra were recorded on a JASCO V-560 spectrometer. Fluorescence spectra were recorded on a JASCO FP-6500 spectrometer. Circular dichroism (CD) spectra were recorded on a JASCO J-1500 spectrophotometer. Atomic force microscopy (AFM) measurements were carried out by using an Agilent 5100 microscope in air at ambient temperature with standard silicon cantilevers (NCH, NanoWorld, Neuchatel, Switzerland). The Pico Image processing program was used for the image analysis. Optical rotations were recorded on a JASCO DIP-370 polarimeter.

Computational Methods

Semiempirical molecular orbital theory calculations were performed using Gaussian 16.⁸⁴ Molecular geometries were optimized at the PM6 level. The Chimera program was used to visualize the molecular structures.⁸⁵

Experimental Procedures

(R,R)-3: To a solution of (R)-2 (3.87 g, 19.1 mmol) in dry THF (183 mL), triethylamine (2.70 mL, 19.3 mmol) and α,α′-dibromo-p-xylene (1.26 g, 4.77 mmol) were added at 0 °C under argon atmosphere. After stirring at room temperature for 12 h, the resultant reaction mixtures were poured into water and extracted with dichloromethane. The organic layer was concentrated in vacuo. Chromatographic purification of the crude product was performed on silica gel (30% ethyl acetate–hexane) to give (R,R)-3 (1.02 g, 43%) as a colorless oil. |$[\alpha ]_{\text{D}}^{25}$| = −28 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); ¹H NMR (300 MHz, chloroform-d₁): δ 7.31 (s, 4H), 5.15, 5.11 (ABq, 4H, J = 12.7 Hz), 4.86 (q, J = 7.2 Hz, 1H), 4.46 (q, J = 7.2 Hz, 1H), 2.84 (s, 3H), 2,78 (s, 3H), 1.44 (s, 9H), 1.40 (d, 6H, J = 7.6 Hz), 1.38 (s, 9H) ppm; ¹³C{¹H} NMR (75 MHz, chloroform-d₁): δ 172.3, 156.0, 155.4, 135.8, 128.2, 80.4, 80.2, 66.4, 55.3, 53.8, 31.3, 30.7, 28.4, 15.4, 14.9 ppm; FTIR-ATR (neat): ν 1740, 1691 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M + Na]⁺ Calcd for C₂₆H₄₀O₈N₂Na 531.2677; found 531.2667.

(S,S)-3: To a solution of (S)-2 (2.36 g, 11.6 mmol) in dry THF (112 mL), triethylamine (1.65 mL, 11.8 mmol) and α,α′-dibromo-p-xylene (769 mg, 2.91 mmol) were added at 0 °C under argon atmosphere. After the mixture was stirred at room temperature for 12 h, a small portion of water was added, and extraction was performed with dichloromethane. The organic layer was concentrated in vacuo. Chromatographic purification of the crude product was performed on silica gel (30% ethyl acetate–hexane) to give (S,S)-3 (646 mg, 44%) as a colorless oil. |$[\alpha ]_{\text{D}}^{25}$| = +28 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); ¹H NMR (300 MHz, chloroform-d₁): δ 7.32 (s, 4H), 5.16, 5.12 (ABq, 4H, J = 12.8 Hz), 4.87 (q, J = 7.2 Hz, 1H), 4.47 (q, 1H, J = 7.2 Hz), 2.85 (s, 3H), 2,79 (s, 3H), 1.45 (s, 9H), 1.42 (d, 6H, J = 7.2 Hz), 1.38 (s, 9H) ppm; ¹³C{¹H} NMR (75 MHz, chloroform-d₁): δ 172.3, 156.0, 155.4, 135.8, 128.2, 80.4, 80.2, 66.4, 55.3, 53.8, 31.3, 30.7, 28.4, 15.4, 14.9 ppm; FTIR-ATR (neat): ν 1741, 1691 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M + Na]⁺ Calcd for C₂₆H₄₀O₈N₂Na 531.2677; found 531.2671.

(R,R)-4: A mixture of (R,R)-3 (100 mg, 0.12 mmol) in 4 M hydrochloric acid dioxane solution (6 mL) was stirred under a nitrogen atmosphere. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo to give (R,R)-4 as a white solid (30 mg, 40%). |$[\alpha ]_{\text{D}}^{25}$| = −28 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); M.p. 189–191 °C; ¹H NMR (300 MHz, methanol-d₄): δ 7.47 (s, 4H), 5.34, 5.29 (ABq, 4H, J = 12.3 Hz), 4.15 (q, 2H, J = 7.3 Hz), 2.74 (s, 6H), 1.57 (d, 6H, J = 7.3 Hz) ppm; ¹³C{¹H} NMR (75 MHz, methanol-d₄): δ 170.4, 137.0, 129.9, 68.8, 57.4, 31.6, 14.5 ppm; FTIR-ATR (neat): ν 1741 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M − 2(Cl⁻)]^2+• Calcd for C₁₆H₂₆O₄N₂ 155.0941; found 155.0939.

(S,S)-4: A mixture of (S,S)-3 (50 mg, 0.98 mmol) in 4 M hydrochloric acid dioxane solution (6 mL) was stirred under a nitrogen atmosphere. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo to give (S,S)-4 as a white solid (23 mg, 60%). |$[\alpha ]_{\text{D}}^{25}$| = +28 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); M.p. 187–189 °C; ¹H NMR (300 MHz, methanol-d₄): δ 7.47 (s, 4H), 5.34, 5.29 (ABq, 4H, J = 12.2 Hz), 4.14 (q, 2H, J = 7.3 Hz), 2.74 (s, 6H), 1.57 (d, 6H, J = 7.3 Hz) ppm; ¹³C{¹H} NMR (75 MHz, methanol-d₄): δ 170.4, 137.0, 129.9, 68.8, 57.5, 31.6, 14.5 ppm; FTIR-ATR (neat): ν 1740 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M − 2(Cl⁻)]^2+• Calcd for C₁₆H₂₆O₄N₂ 155.0941; found 155.0939.

(R,R)-G1: Silver hexafluorophosphate (39 mg, 0.16 mmol) in acetonitrile (5 mL) was added to a solution of (R,R)-3 (30 mg, 0.078 mmol) in methanol (5 mL). After stirring for 30 min, the precipitate was filtered off, and the filtrate was concentrated in vacuo to give (R,R)-G1 as a colorless oil (40 mg, 84%). |$[\alpha ]_{\text{D}}^{25}$| = −27 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); ¹H NMR (300 MHz, methanol-d₄): δ 7.46 (s, 4H), 5.33, 5.29 (ABq, 4H, J = 12.2 Hz), 4.12 (q, 2H, J = 7.3 Hz), 2.74 (s, 6H), 1.56 (d, 6H, J = 7.3 Hz) ppm; ¹³C{¹H} NMR (75 MHz, methanol-d₄): δ 170.4, 136.9, 129.9, 68.8, 57.5, 31.6, 14.5 ppm; FTIR-ATR (neat): ν 1738 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M − 2(PF₆⁻)]²⁺ Calcd for C₁₆H₂₆O₄N₂ 155.0941; found 155.0942.

(S,S)-G1: Silver hexafluorophosphate (13 mg, 0.051 mmol) in acetonitrile (5 mL) was added to a solution of (S,S)-3 (10 mg, 0.026 mmol) in methanol (5 mL). After stirring for 30 min, the precipitate was filtered off, and the filtrate was concentrated in vacuo to give (S,S)-G1 as a colorless oil (15 mg, 95%). |$[\alpha ]_{\text{D}}^{25}$| = +27 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); ¹H NMR (300 MHz, methanol-d₄): δ 7.46 (s, 4H), 5.34, 5.29 (ABq, 4H, J = 12.2 Hz), 4.12 (q, 2H, J = 7.3 Hz), 2.74 (s, 6H), 1.56 (d, 6H, J = 7.3 Hz) ppm; ¹³C{¹H} NMR (75 MHz, methanol-d₄): δ 170.5, 136.9, 129.9, 68.8, 57.5, 31.6, 14.5 ppm; FTIR-ATR (neat): ν 1738 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M − 2(PF₆⁻)]²⁺ Calcd for C₁₆H₂₆O₄N₂ 155.0941; found 155.0940.

(S)-5: To a solution of (S)-2 (5.42 g, 17.1 mmol) in dry THF (170 mL), triethylamine (2.38 mL, 17.1 mmol) and benzylbromide (1.47 g, 8.60 mmol) were added at 0 °C under argon atmosphere. After the mixture was stirred at room temperature for 10 h, a small portion of water was added, and extraction was performed with dichloromethane. The organic layer was concentrated in vacuo. Chromatographic purification of the crude product was performed on silica gel (30% ethyl acetate–hexane) to give (S)-5 (1.70 g, 63%) as a colorless oil. |$[\alpha ]_{\text{D}}^{25}$| = 25 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); ¹H NMR (300 MHz, chloroform-d₁): δ 7.34 (s, 5H), 5.15 (s, 2H), 4.89 (q, J = 7.2 Hz, 0.5H), 4.48 (q, J = 7.2 Hz, 0.5H), 2.86 (s, 1.5H), 2.78 (s, 1.5H), 1.45 (s, 4.5H), 1.42 (d, 3H, J = 7.2 Hz), 1.38 (s, 4.5H) ppm; ¹³C{¹H} NMR (75 MHz, chloroform-d₁): δ 172.4, 156.1, 135.9, 128.7, 128.4, 128.3, 128.1, 80.4, 80.2, 66.8, 55.3, 53.7, 31.3, 30.6, 28.5, 15.4, 14.9 ppm; FTIR-ATR (neat): ν 1742 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M + Na]⁺ Calcd for C₁₆H₂₃O₄NNa 316.1519; found 316.1521.

(S)-6: A mixture of (S)-5 (20 mg, 0.063 mmol) in 4 M hydrochloric acid dioxane solution (4 mL) was stirred under a nitrogen atmosphere. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo to give (S)-6 as a white solid (10 mg, 69%). |$[\alpha ]_{\text{D}}^{25}$| = +25 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); M.p. 201–204 °C; ¹H NMR (300 MHz, methanol-d₄): δ 7.41–7.36 (m, 5H), 5.33, 5.28 (ABq, 2H, J = 12.1 Hz), 4.12 (q, 1H, J = 7.2 Hz), 2.73 (s, 3H), 1.56 (d, 3H, J = 7.2 Hz) ppm; ¹³C{¹H} NMR (75 MHz, methanol-d₄): δ 170.4, 136.4, 129.8, 129.7, 129.7, 69.3, 57.5, 31.6, 14.5 ppm; FTIR-ATR (neat): ν 1728 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M]⁺ Calcd for C₁₁H₁₆O₂N 194.1176; found 194.1175.

(S)-G2: Silver hexafluorophosphate (12 mg, 0.047 mmol) in acetonitrile (5 mL) was added to a solution of (S)-6 (10 mg, 0.043 mmol) in methanol (5 mL). After stirring for 30 min, the precipitate was filtered off, and the filtrate was concentrated in vacuo to give (S)-G2 as a colorless oil (14 mg, 97%). |$[\alpha ]_{\text{D}}^{25}$| = +24 cm³ g⁻¹ dm⁻¹ (c 0.01 g cm⁻³); ¹H NMR (300 MHz, methanol-d₄): δ 7.42–7.35 (m, 5H), 5.32, 5.27 (ABq, 2H, J = 12.2 Hz), 4.09 (q, 1H, J = 7.3 Hz), 2.73 (s, 3H), 1.55 (d, 3H, J = 7.3 Hz) ppm; ¹³C{¹H} NMR (75 MHz, methanol-d₄): δ 170.5, 136.3, 129.8, 129.7, 129.7, 69.3, 57.5, 31.6, 14.5 ppm; FTIR-ATR (neat): ν 1739 cm⁻¹; HRMS (ESI-Orbitrap) m/z: [M]⁺ Calcd for C₁₁H₁₆O₂N 194.1176; found 194.1175.

Acknowledgment

This work was supported by Grants-in-Aid for Scientific Research (A), JSPS KAKENHI Grant Number JP21H04685, Grant-in-Aid for Challenging Research (Exploratory), JSPS KAKENHI Grant Number JP20K21196, Grants-in-Aid for Scientific Research on Innovative Areas, JSPS KAKENHI Grant Number JP21H05491 (Condensed Conjugation), and Grant-in-Aid for Young Scientists, JSPS KAKENHI Grant Number 20K15335. We also thank the Natural Science Center for Basic Research Development (N-BARD) and Hiroshima University for crystallographic analysis. D.S. thanks the Grant-in-Aid for JSPS Fellows, JSPS KAKENHI Grant Number JP 18J13703.

Supporting Information

¹H NMR spectra, ¹³C NMR spectra, HRMS spectra, and IR spectra, VT NMR spectra, ITC curves, Job plot, diffusion coefficient values, AFM images, and cartesian coordinates of a calculated structure. This material is available on https://doi.org/10.1246/bcsj.20210452.

Koki Hamada

Koki Hamada is a graduate student of Hiroshima University. He has received a B.S. degree from Hiroshima University in 2021 under the supervision of prof. Haino. His current study focuses on the development of supramolecular architectures that contain molecular capsules.

Takeharu Haino

Takeharu Haino received his Ph.D. degree from Hiroshima University in 1992. He moved to Sagami Chemical Research Center. In 1993, he was appointed as an Assistant Professor to the Department of Chemistry at Hiroshima University. He joined the group of Professor Julius Rebek, Jr. at The Scripps Research Institute (1999–2000). He was promoted to an Associate Professor in 2000 and to Full Professor in 2007 and is now a distinguished professor. His research interests encompass functional supramolecular assemblies and polymers, and functional graphenes.